BACKGROUND: Focal segmental glomerulosclerosis (FSGS), a histologic pattern of injury in the glomerulus, is one of the leading glomerular causes of end-stage renal disease (ESRD) worldwide. Despite extensive research, the underlying biological alterations causing FSGS remain poorly understood. Studying variations in gene expression profiles offers a promising approach to gaining a comprehensive understanding of FSGS molecular pathogenicity and identifying key elements as potential therapeutic targets. This work is a meta-analysis of gene expression profiles from glomerular samples of FSGS patients. The main aims of this study are to establish a consensus list of differentially expressed genes in FSGS, validate these findings, understand the disease\'s pathogenicity, and identify novel therapeutic targets.
METHODS: After a thorough search in the GEO database and subsequent quality control assessments, seven gene expression datasets were selected for the meta-analysis: GSE47183 (GPL14663), GSE47183 (GPL11670), GSE99340, GSE108109, GSE121233, GSE129973, and GSE104948. The random effect size method was applied to identify differentially expressed genes (meta-DEGs), which were then used to construct a regulatory network (STRING, MiRTarBase, and TRRUST) and perform various pathway enrichment analyses. The expression levels of several meta-DEGs, specifically ADAMTS1, PF4, EGR1, and EGF, known as angiogenesis regulators, were analyzed using quantitative reverse transcription polymerase chain reaction (RT-qPCR).
RESULTS: The identified 2,898 meta-DEGs, including 665 downregulated and 669 upregulated genes, were subjected to various analyses. A co-regulatory network comprising 2,859 DEGs, 2,688 microRNAs (miRNAs), and 374 transcription factors (TFs) was constructed, and the top molecules in the network were identified based on degree centrality. Part of the pathway enrichment analysis revealed significant disruption in the angiogenesis regulatory pathways in the FSGS kidney. The RT-qPCR results confirmed an imbalance in angiogenesis pathways by demonstrating the differential expression levels of ADAMTS1 and EGR1, two key angiogenesis regulators, in the FSGS condition.
CONCLUSIONS: In addition to presenting a consensus list of differentially expressed genes in FSGS, this meta-analysis identified significant distortions in angiogenesis-related pathways and factors in the FSGS kidney. Targeting these factors may offer a viable strategy to impede the progression of FSGS.

UNASSIGNED: Psoriatic arthritis (PsA) is a debilitating chronic condition characterized by inflammation of the joints, bones, enthesis, and skin. The pivotal role of interleukin-23 (IL-23) in the pathogenesis of PsA has become increasingly evident. This proinflammatory cytokine is markedly elevated in patients with PsA, suggesting its potential as a therapeutic target. Consequently, IL-23 inhibitors have emerged as promising first-line biologic treatments for PsA.
UNASSIGNED: This review delves into the immunopathogenic mechanisms of IL-23 at the cellular and molecular levels in PsA. Furthermore, it provides the recent efficacy and safety profiles of IL-23 inhibitors. We conducted a literature search in PubMed for the following terms: \'IL-23 and psoriatic arthritis,\' \'Ustekinumab,\' \'Guselkumab,\' \'Risankizumab,\' and \'Tildrakizumab.\' In addition, we retrieved clinical trials involving IL-23 inhibitors registered in ClinicalTrials.gov, EudraCT, and ICTRP.
UNASSIGNED: Despite the promising outcomes observed with IL-23 inhibitors, several challenges persist. The long-term effects of these agents require further investigation through prospective studies, and their limited accessibility worldwide necessitates urgent attention. Additionally, ongoing research is warranted to explore other potential drug targets within the IL-23/IL-23 R axis. The development of reliable biomarkers could greatly enhance early detection, tailored management strategies, and personalized treatment approaches for patients with PsA.

Long non-coding RNAs (lncRNAs) have been identified as important participants in several biological functions, particularly their complex interactions with the KRAS pathway, which provide insights into the significant roles lncRNAs play in cancer development. The KRAS pathway, a central signaling cascade crucial for cell proliferation, survival, and differentiation, stands out as a key therapeutic target due to its aberrant activation in many human cancers. Recent investigations have unveiled a myriad of lncRNAs, such as H19, ANRIL, and MEG3, intricately modulating the KRAS pathway, influencing both its activation and repression through various mechanisms, including epigenetic modifications, transcriptional regulation, and post-transcriptional control. These lncRNAs function as fine-tuners, delicately orchestrating the balance required for normal cellular function. Their dysregulation has been linked to the development and progression of multiple malignancies, including lung, pancreatic, and colorectal carcinomas, which frequently harbor KRAS mutations. This scrutiny delves into the functional diversity of specific lncRNAs within the KRAS pathway, elucidating their molecular mechanisms and downstream effects on cancer phenotypes. Additionally, it underscores the diagnostic and prognostic potential of these lncRNAs as indicators for cancer detection and assessment. The complex regulatory network that lncRNAs construct within the context of the KRAS pathway offers important insights for the creation of focused therapeutic approaches, opening new possibilities for precision medicine in oncology. However, challenges such as the dual roles of lncRNAs in different cancer types and the difficulty in therapeutically targeting these molecules highlight the ongoing debates and need for further research. As ongoing studies unveil the complexities of lncRNA-mediated KRAS pathway modulation, the potential for innovative cancer interventions becomes increasingly promising.

The compilation of ligand and structure-based molecular modeling methods has become an important practice in virtual screening applied to drug discovery. This systematic review addresses and ranks various virtual screening strategies to drive the selection of the optimal method for studies that have as their starting point a multi-ligand investigation and investigation based on the protein structure of a therapeutic target. This study shows examples of applications and an evaluation based on the objective and problematic of a series of virtual screening studies present in the ScienceDirect® database. The results showed that the molecular docking technique is widely used in scientific production, indicating that approaches that use protein structure as a starting point are the most promising strategy for drug discovery that relies on virtual screening-based research.

Progranulin (PGRN), a multifunctional growth factor-like protein expressed by a variety of cell types, serves an important function in the physiologic and pathologic processes of fibrotic diseases, including wound healing and the inflammatory response. PGRN was discovered to inhibit pro-inflammation effect by competing with tumor necrosis factor-alpha (TNF-α) binding to TNF receptors. Notably, excessive tissue repair in the development of inflammation causes tissue fibrosis. Previous investigations have indicated the significance of PGRN in regulating inflammatory responses. Recently, multiple studies have shown that PGRN was linked to fibrogenesis, and was considered to monitor the formation of fibrosis in multiple organs, including liver, cardiovascular, lung and skin. This paper is a comprehensive review summarizing our current knowledge of PGRN, from its discovery to the role in fibrosis. This is followed by an in-depth look at the characteristics of PGRN, consisting of its structure, basic function and intracellular signaling. Finally, we will discuss the potential of PGRN in the diagnosis and treatment of fibrosis.

Acute pancreatitis (AP) is a potentially fatal condition with no targeted treatment options. Although inhibiting xanthine oxidase (XO) in the treatment of AP has been studied in several experimental models and clinical trials, whether XO is a target of AP and what its the main mechanism of action is remains unclear. Here, we aimed to re-evaluate whether XO is a target aggravating AP other than merely generating reactive oxygen species that trigger AP. We first revealed that XO expression and enzyme activity were significantly elevated in the serum and pancreas of necrotizing AP models. We also found that allopurinol and febuxostat, as purine-like and non-purine XO inhibitors, respectively, exhibited protective effects against pancreatic acinar cell death in vitro and pancreatic damage in vivo at different doses and treatment time points. Moreover, we observed that conditional Xdh overexpression aggravated pancreatic necrosis and severity. Further mechanism analysis showed that XO inhibition restored the hypoxia-inducible factor 1-alpha (HIF-1α)-regulated lactate dehydrogenase A (LDHA) and NOD-like receptor family pyrin domain containing 3 (NLRP3) signaling pathways and reduced the enrichment of 13C6-glucose to 13C3-lactate. Lastly, we observed that clinical circulatory XO activity was significantly elevated in severe cases and correlated with C-reactive protein levels, while pancreatic XO and urate were also increased in severe AP patients. These results together indicated that proper inhibition of XO might be a promising therapeutic strategy for alleviating pancreatic necrosis and preventing progression of severe AP by downregulating HIF-1α-mediated LDHA and NLRP3 signaling pathways.

BACKGROUND: The cancer genome contains several driver mutations. However, in some cases, no known drivers have been identified; these remaining areas of unmet needs, leading to limited progress in cancer therapy. Whole-genome sequencing (WGS) can identify non-coding alterations associated with the disease. Consequently, exploration of non-coding regions using WGS and other omics data such as ChIP-sequencing (ChIP-seq) to discern novel alterations and mechanisms related to tumorigenesis have been attractive these days.
METHODS: Integrated multi-omics analyses, including WGS, ChIP-seq, DNA methylation, and RNA-sequencing (RNA-seq), were conducted on samples from patients with non-clinically actionable genetic alterations (non-CAGAs) in lung adenocarcinoma (LUAD). Second-level cluster analysis was performed to reinforce the correlations associated with patient survival, as identified by RNA-seq. Subsequent differential gene expression analysis was performed to identify potential druggable targets.
RESULTS: Differences in H3K27ac marks in non-CAGAs LUAD were found and confirmed by analyzing RNA-seq data, in which mastermind-like transcriptional coactivator 2 (MAML2) was suppressed. The down-regulated genes whose expression was correlated to MAML2 expression were associated with patient prognosis. WGS analysis revealed somatic mutations associated with the H3K27ac marks in the MAML2 region and high levels of DNA methylation in MAML2 were observed in tumor samples. The second-level cluster analysis enabled patient stratification and subsequent analyses identified potential therapeutic target genes and treatment options.
CONCLUSIONS: We overcome the persistent challenges of identifying alterations or driver mutations in coding regions related to tumorigenesis through a novel approach combining multi-omics data with clinical information to reveal the molecular mechanisms underlying non-CAGAs LUAD, stratify patients to improve patient prognosis, and identify potential therapeutic targets. This approach may be applicable to studies of other cancers with unmet needs.

The limited understanding of the molecular mechanism underlying MYCN-amplified (MNA) neuroblastoma (NB) has hindered the identification of effective therapeutic targets for MNA NB, contributing to its higher mortality rate compared to MYCN non-amplified (non-MNA) NB. Therefore, a comprehensive analysis integrating metabolomics and transcriptomics was conducted to systematically investigate the MNA NB. Metabolomics analysis utilized plasma samples from 28 MNA NB patients and 68 non-MNA NB patients, while transcriptomics analysis employed tissue samples from 15 MNA NB patients and 37 non-MNA NB patients. Notably, joint metabolomics and transcriptomics analysis was performed. A total of 46 metabolites exhibited alterations, with 21 displaying elevated levels and 25 demonstrating reduced levels in MNA NB. In addition, 884 mRNAs in MNA NB showed significant changes, among which 766 mRNAs were higher and 118 mRNAs were lower. Joint-pathway analysis revealed three aberrant pathways involving glycerolipid metabolism, purine metabolism, and lysine degradation. This study highlights the substantial differences in metabolomics and transcriptomics between MNA NB and non-MNA NB, identifying three abnormal metabolic pathways that may serve as potential targets for understanding the molecular mechanisms underlying MNA NB.

Inositol 1,4,5-Trisphosphate Receptor-Interacting Protein-Like 1 (ITPRIPL1), a single-pass type I membrane protein located in the membrane, functions as an inhibitory ligand of CD3ε. Recent studies have shown that its expression suppresses T cells activation and promote tumor immune evasion. Despite increasing evidence suggesting that ITPRIPL1 plays a significant role in tumor growth, no systematic pan-cancer analysis of ITPRIPL1 has been conducted to date. This study utilized datasets curated from The Cancer Genome Atlas, Genotype Tissue-Expression, and Human Protein Atlas to investigate the relationship between ITPRIPL1 expression and clinical outcomes, immune infiltration, and drug sensitivity across 33 cancer types. We employed multiple methods to assess its prognostic value in pan-cancer, such as univariate Cox regression, survival analysis, and ROC curve analysis and explored the relationship between ITPRIPL1 and tumor mutation burden (TMB), tumor microsatellite instability (MSI), CNV, DNA methylation, immune-related genes, immune cell infiltration, and drug sensitivity to reveal its immunological role. The mRNA expression levels of the ITPRIPL1 gene vary significantly across multiple types of cancer and significantly reduced in breast cancer. Conversely, high ITPRIPL1 expression was associated with a better prognosis in BRCA. Furthermore, the expression of ITPRIPL1 highly correlates with the presence of tumor-infiltrating immune cells and immune checkpoint genes across various types of cancers. Additionally, ITPRIPL1 expression was associated with TMB in 6 cancer types and with MSI in 13 cancer types. High expression of ITPRIPL1 serves as a protective factor in certain cancer types, correlating with longer overall survival in BRCA. Our study further confirms that ITPRIPL1 participates in regulating immune infiltration and affecting the prognosis of patients in pan-cancer. These findings underscore the promising potential of ITPRIPL1 as a therapeutic target for human cancer.

Liver cancer is one of the most lethal gastrointestinal malignancies. Emerging evidence has underscored the pivotal role of long non-coding RNAs (lncRNAs) in tumorigenesis, with ST8SIA6-AS1 identified as a novel oncogenic lncRNA contributing to liver cancer progression. ST8SIA6-AS1 is consistently upregulated in hepatic cancer tissues and is strongly associated with unfavorable prognosis. Moreover, it demonstrates high diagnostic efficacy in detecting HCC. ST8SIA6-AS1 is involved in various cellular processes including proliferation, migration, and invasion, primarily through its function as a competing endogenous RNA (ceRNA), thereby facilitating hepatocarcinogenesis and disease advancement. This review provides a detailed examination of the molecular functions and regulatory mechanisms of ST8SIA6-AS1 in hepatocellular carcinoma (HCC) and highlights its potential as a promising biomarker for liver cancer, aiming to propel the development of innovative therapeutic strategies for HCC management.